The present invention relates to o-anisamide derivatives effective for the prevention and/or therapy of metabolic diseases such as hyperlipidemia and diabetes, in which peroxisome proliferator-activated receptor (PPAR) being intranuclear receptor, in particular, human PPAR participates, as agonistic drugs thereon, their addition salts, processes for preparing them, and medicinal compositions containing these compounds.
The peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription factor that belongs to intranuclear receptor superfamily similarly to steroid receptor, retinoid receptor, thyroid receptor, etc., and three isoforms (xcex1 type, xcex2(or xcex4) type and xcex3 type) with different histological distribution have been identified hitherto in human and various animal species (Proc. Natl. Acad. Sci., 1992, 89, 4653). There among, the PPARxcex1 is distributed in the liver, kidney, etc. with high catabolic capacity for fatty acids and, particularly in the liver, high expression is recognized (Endocrinology, 1995, 137, 354), positively or negatively controlling the expressions of genes relevant to the metabolism and the intracellular transport of fatty acids (e.g. acyl CoA synthetic enzyme, fatty acid-binding protein and lipoprotein lipase) and apolipoprotein (AI, AII, CIII) genes relevant to the metabolisms of cholesterol and triglyceride. Moreover, the PPARxcex3 is highly expressed in the fat cells and takes part in the differentiation of fat cells (J. Lipid Res., 1996, 37, 907), and so on. In such way, each isoform of PPAR is fulfilling a specific function in the particular organs and tissues.
Additionally, it is reported that a knock-out mouse of PPARxcex1 exhibits hyper triglyceridemia with ageing and becomes obesity mainly by increased white adipocytes (J. Biol. Chem., 1998, 273, 29577), hence the relevance between activation of PPARa and lowering action of lipids (cholesterol and triglyceride) in blood is suggested strongly. Similarly, it is ascertained that the major intracellular target proteins of Troglitazone, Pioglitazone and Rosiglitazone being thiazolidine-2,4-dione derivatives that exhibit blood glucose-lowering action and improving action on hyperinsulinemia are PPARxcex3s, and they increase the transcriptional activity of PPARxcex3 (Endocrinology, 1996, 137, 4189, Cell., 1995, 83, 803 and 813). Hence, the relevance between activation of PPARxcex3 and glucose-lowering action is suggested strongly.
When considering such functions of transcriptional factor called PPAR, for a compound that activates human PPAR, medicinal use aiming at the lowering action of lipids (cholesterol and triglyceride) in blood and/or the blood glucose-lowering action can be expected.
For compounds having an affinity to PPARxcex1 as ligands of PPARxcex1, eicosanoides, in particular, 8-hydroxyeicosatetraenoic acid (8-HETE) and 8-hydroxyeicosapentaenoic acid (8-HEPE) are reported (Proc. Natl. Acad. Sci., 1997, 94, 312).
However, these endogenous unsaturated fatty acid derivatives are unstable and difficult to be offered as medicinal drugs, and, at the same time, they have different structure from the inventive compounds. Moreover, compounds having agonistic action on PPARxcex1 are reported in WO-97/25042, WO-97/36579, etc., but all of these have different structure from the inventive compounds and, at the same time, the effect of agonistic action is also never satisfied in strength. For compounds having agonistic action on PPARxcex3, a series of thiazolidine-2,4-dione derivatives are known in Japanese Unexamined Patent Publication Nos. Sho 60-51189, Sho 61-267580, Hei 1-131169, etc. However, all have different structure from the inventive compounds.
It is pointed out that the hyperlipidemia and the diabetes are principal diseases that modern times have to tackle and, at the same time, these become risk factors and link up with the atherosclerotic diseases, in particular, coronary atherosclerotic disease. Hence, from a viewpoint of the therapy or prevention thereof, the development of a therapeutic drug for metabolic diseases being effective and having high safety based on new action is desired strongly.
As a result of diligent studies paying an attention to the specific roles on the lipometabolism, adipocyte differentiation, of human PPAR, and aiming at the creation of structurally novel drug with high effectiveness and safety as a therapeutic drug for metabolic diseases, the inventors have found that o-anisamide derivatives represented by a following general formula (1) have excellent agonistic action on human PPAR and are useful as therapeutic drugs for metabolic diseases, leading to the completion of the invention.
Namely, the invention relates to o-anisamide derivatives represented by a general formula (1) 
[wherein R denotes a carboxyl group, carboxymethyl group or CH2CHXCOY (here X denotes a mercapto group or S(O)nMe (n=0, 1 or 2) and Y denotes an amino group or hydroxyl group)], their medicinally acceptable salts and their hydrates.
The medicinally acceptable salts of the compounds represented by the general formula (1) in the invention are of common use and metal salts, for example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.) and aluminum salt are mentioned.
Moreover, the compounds, R being CH2CHXCOY, in the general formula (1) of the invention include optically active substances based on asymmetric carbon, and further, in the case of X being SOMe group, they include stereoisomers based on their three dimensions, but all of these isomers and mixtures are to be included in the scope of the invention.
According to the invention, compounds (1), being said general formula (1), can be prepared through processes shown in following diagram. 
Namely, compounds represented by a general formula (1-a) can be prepared by condensation, leaving carboxyl group as it is or after converted it to reactive derivative according to usual method in the process shown in the diagram above.
In the case of conducting the reaction by leaving carboxylic acid as it is, the reaction can be performed in an inert solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, and further in the presence or absence of additive. As the condensing agent, for example, dicyclohexylcarbodiimide,l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphonate, diphenylphosphoryl azide, carbonyldiimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned.
In the case of using reactive derivative, the reaction can be performed in an inert solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base. As the reactive derivative, acid chloride, acid bromide, acid anhydride, carbonylimidazole or the like can be mentioned. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to room temperature.
Compounds represented by a general formula (1-b) can be prepared by oxidation using usual oxidizing agent, followed by, if need be, hydrolysis. Namely, in the case of R1 being formyl group, the reaction can be performed using usual oxidizing agent, for example, chromium oxide, potassium permanganate, silver oxide or peroxide, but the oxidation using Jones reagent that uses chromic acid is preferable. The reaction temperature is preferable to be under cooling with ice to room temperature. In the case of R1 being cyanomethyl group, the reaction can be performed using peroxide, acid and base, but it is preferable to use acid such as concentrated sulfuric acid or concentrated hydrochloric acid, hydrogen peroxide or the like to convert to carbamoylmethyl group, followed by hydrolysis using base such as sodium hydroxide or potassium hydroxide. The reaction can be performed at a reaction temperature of 50xc2x0 C. to refluxing temperature of solvent in a reaction solvent of alcohol-water system (methanol, ethanol or the like).
Compound, X2 being methylthio group in a general formula (1-d), and compounds represented by a general formula (1-e) can be prepared by converting compound, R1 being nitro group among the compounds represented by the general formula (1-a), to reduced amino form (1-c) in an organic solvent such as ethanol, ethyl acetate or N,N-dimethylformamide at room temperature to under heating at ambient pressure to 329 kPa in the presence of catalyst such as palladium on carbon, followed by Meerwein arylation reaction, and further by reacting with NaSMe. Namely, the Meerwein arylation reaction can be conducted by diazotizing the amino form obtained by reduction with nitrite such as sodium nitrite in an organic solvent, for example, alcohol such as methanol or ethanol, ketone such as acetone or methyl ethyl ketone, water or mixture of these in the presence of hydrogen halide such as hydrochloric acid or hydrobromic acid, and then by reacting catalytic quantity of cuprous salt such as cuprous oxide or cuprous chloride in the presence of acrylamide or acrylic ester (methyl, ethyl, benzyl ester or the like). Further, the methylthio conversion can be performed by heating to by refluxing in an organic solvent, for example, alcohol solvent such as methanol or ethanol in the presence of NaSMe. Moreover, (1-e) being ester form can be derived to corresponding carboxylic acid form by hydrolyzing under a temperature condition of room temperature to refluxing in the presence of base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or acid such as hydrochloric acid or sulfuric acid. Moreover, in the case of X2 being acetylthio group in the general formula (1-d), this can be prepared by conducting Meerwein arylation reaction of amino form (1-c), and then by reacting with potassium thioacetate. The reaction can be performed at room temperature to 50xc2x0 C. in an organic solvent, for example, tetrahydrofuran, dioxane or the like.
Compounds, X3 being methylsulfinyl or methylsulfonyl in a general formula (1-f), and compounds represented by a general formula (1-g) can be prepared by oxidizing corresponding compound, X2 being methylthio group in the general formula (1-d), and compounds represented by the general formula (1-e) using peroxide, respectively, and, if need be, by hydrolyzing. As the peroxide, aqueous hydrogen peroxide, perbenzoic acid, peracetic acid, m-chloroperbenzoic acid (mCPBA) or the like can be mentioned. The reaction can be performed under cooling with ice to at room temperature in an organic solvent, for example, methylene chloride, chloroform, ethyl acetate or the like. Moreover, the sulfonyl form (n=2) can be obtained directly using excess peroxide, but it can also be obtained by further oxidizing sulfinyl form (n=1) similarly after obtaining this. Moreover, the ester form can be derived to corresponding carboxylic acid form (1-g) by hydrolyzing under a temperature condition of room temperature to refluxing in the presence of base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or acid such as hydrochloric acid or sulfuric acid. Similarly, in the case of X3 being mercapto group in the general formula (1-f), it is possible to derive to corresponding mercapto form by hydrolyzing corresponding compound, X2 being acetylthio group in the general formula (1-d), under a temperature condition of cooling with ice to room temperature in the presence of base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or ammonia or acid such as hydrochloric acid or sulfuric acid.
Furthermore, the stereoisomer that can be seen in the sulfinyl form (1-f, n=1) can also be obtained by asymmetric oxidation, for example, by stereoselective oxidation using an optically active ligand such as Davis reagent (J. Am. Chem. Soc., 1992, 114, 1428) or a salen complex.
As the administering form of the inventive compounds, oral administration such as with tablet, capsule, granule, powder, inhalant, syrup or the like, or parenteral administration such as with injection, suppository or the like can be mentioned.
Best embodiment to put the invention into practice In following, the invention will be illustrated based on concrete examples, but the invention is not confined to these examples.